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- Herausgeber: John Wiley & Sons
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- Sprache: Englisch
Impact of Engineered Nanomaterials in Genomics and Epigenomics Overview of current research and technologies in nanomaterial science as applied to omics science at the single cell level Impact of Engineered Nanomaterials in Genomics and Epigenomics is a comprehensive and authoritative compilation of the genetic processes and instructions that specifically direct individual genes to turn on or off, focusing on the developing technologies of engineering nanomaterials and their role in cell engineering which have become important research tools for pharmaceutical, biological, medical, and toxicological studies. Combining state-of-the art information on the impact of engineered nanomaterials in genomics and epigenomics, from a range of internationally recognized investigators from around the world, this edited volume offers unique insights into the current trends and future directions of research in this scientific field. Impact of Engineered Nanomaterials in Genomics and Epigenomics includes detailed information on sample topics such as: * Impact of engineered nanomaterials in genomics and epigenomics, including adverse impact on glucose energy metabolism * Toxicogenomics, toxicoepigenomics, genotoxicity and epigenotoxicity, and mechanisms of toxicogenomics and toxicoepigenomics * Adverse effects of engineered nanomaterials on human environment and metabolomics pathways leading to ecological toxicity * Meta-analysis methods to identify genomic toxicity mechanisms of engineered nanomaterials and biological effects of engineered nanomaterial exposure * Artificial intelligence and machine learning of single-cell transcriptomics of engineered nanoparticles and trends in plant nano-interaction to mitigate abiotic stresses This comprehensive work is a valuable and excellent source of authoritative and up-to-date information for advanced students and researchers, toxicologists, the drug industry, risk assessors and regulators in academia, industry, and government, as well as for clinical scientists working in hospital and clinical environments.
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Impact of Engineered Nanomaterials in Genomics and Epigenomics
Edited by
Saura C. Sahu Formerly of Center for Food Safety and Applied Nutrition, US Food and Drug Administration, MD, USA
This edition first published 2023
© 2023 John Wiley & Sons Ltd
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Hardback ISBN: 9781119896227; ePub ISBN: 9781119896241; ePDF ISBN: 9781119896234; oBook ISBN: 9781119896258
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Set in 9.5/12.5pt STIXTwoText by Integra Software Services Pvt. Ltd, Pondicherry, India
Dedicated to my family:
My late parents, Gopinath and Ichhamoni, for their gifts of life and love, and for being living examples.
My wife, Jharana, for her life-long friendship, love and support as well as for her patience and understanding of the long hours spent at home on planning, writing, and editing this book.
My children, Meghamala, Sudhir, Subir, and their spouses for their love and care.
My eight-year-old granddaughter, Naomi, and six-year-old grandson, Jonah, for their unconditional love, faith, and trust in me.
Saura C. Sahu, Ph.D.Columbia, Maryland, USAJune 5, 2022
Contents
Cover
Title Page
Copyright
Dedication
List of Contributors
Preface
Acknowledgments
1 Impact of Engineered Nanomaterials in Genomics and Epigenomics
Nanotechnology: A Technological Advancement of the Twenty-First Century
Genomics and Epigenomics
Beneficial Impacts of Engineered Nanomaterials on Human Life
Potential Adverse Health Effects of Engineered Nanomaterials
Conclusions
References
2 Molecular Impacts of Advanced Nanomaterials at Genomic and Epigenomic Levels
Introduction
Classification of NMs
Absorption and Distribution of NMs
Inhalation Exposure
Oral Exposure
Dermal Exposure
Circulatory Distribution
Accumulation of NMs in Organs
Major Adverse Effects of NMs
Known Cellular and Nuclear Uptake Mechanisms for Nanoparticles
Epigenetic Mechanisms and the Effect of NMs
DNA Methylation
Histone Modification
Noncoding RNAs
Genetic and Genomic Effects of NMs
Genetic Damage (Genotoxicity)
Genomic Changes on the Messenger RNA Level
Conclusion
References
3 Endocrine Disruptors: Genetic, Epigenetic, and Related Pathways
Introduction
Toxic Effects of EDCs on Wildlife and Humans
EDCs Effects on Wildlife
Effects During Development
Delayed Effects
Transgenerational Effects
Identification of EDC: Methods
Genetic Pathways
Nuclear Receptor-Mediated Assays
Phosphorylation-Mediated Signaling Pathways of Nuclear Receptors and Other Transcription Factors: Link to EDC
ER-Signaling Pathways
Xenoandrogens and Metabolic Syndrome
AR Signaling Pathways
Mechanism of ED
Epigenetic Mechanism
Methylation and Gene Regulation
Role of Noncoding RNAs
Transgenerational Inheritance of Epigenetics Induced by EDCs
Anti-Thyroids
Organotin
Genomic Signaling and Effects
Epigenetic Effects of Organotin
TCDD and Related Compounds
TCDD and Genetic Response
TCDD-Mediated Epigenetic Response
Conclusions
References
4 Nanoplastics in Agroecosystem and Phytotoxicity: An Evaluation of Cytogenotoxicity and Epigenetic Regulation
Introduction
Fate and Behavior of NPs in Agroecosystem and Soil Environment
Uptake and Accumulation of NPs in Plants
NPs and Phytotoxicity
Morphological and Physiological Responses
Biochemical and Metabolic Responses
Can NPs Cause Cytogenotoxicity and Dysregulate Epigenetic Markers in Plants?
NPs Cause Cytogenotoxicity
NPs and Epigenetic Regulation
Conclusion and Perspectives
References
5 Metal Oxide Nanoparticles and Graphene-Based Nanomaterials: Genotoxic, Oxidative, and Epigenetic Effects
Introduction
Physicochemical Properties of NMs and Toxicity
Mechanism of NM Genotoxicity
Epigenetic Effects of Nanomaterials
Studies on Genotoxic and Oxidative Effects of Metal Oxides and Graphene-Based Nanomaterials
Titanium Dioxide NPs
Zinc Oxide NPs
Silver and Silver Oxide NPs
Copper and Copper Oxide NPs
Cobalt Oxide Nanoparticles
Silicon Dioxide NPs
Graphene-Based NMs
Studies on Epigenetic Effects of Metal Oxides and Graphene-Based Nanomaterials
Metal Oxide Nanomaterials
Graphene-Based Nanomaterials
Studies on Workers – Genotoxic and Oxidative Effects of Occupational Exposure to Meta Oxides Nanoparticles, SiO2 NPs, and Graphene-Based Nanomaterials
Conclusions
References
6 Epigenotoxicity of Titanium Dioxide Nanoparticles
Introduction
Cellular Uptake and Biodistribution
DNA Methylation and TiO2 Nanoparticles
Histone Modifications and TiO2 Nanoparticles
MicroRNAs and TiO2 Nanoparticles
Risk Assessment
Conclusion
Disclaimer
References
7 Toxicogenomics of Multi-Walled Carbon Nanotubes
Introduction
MWCNTs
Lung Injury
Inflammation
Oxidative Stress
Fibrosis
Mesothelioma
Lung Cancer
Genotoxicity
Toxicogenomics of ENMs
Transcriptomics – Technical Aspects
Toxicogenomics of MWCNTs – Animal Studies
Toxicogenomics of MWCNT – Human Studies
Disclaimer
References
8 Nano-Engineering in Traumatic Brain Injury
Introduction
Nanoparticles in the Treatment of TBI
Synthesis of Nanoparticles
Mechanisms of Action of Nanoparticles in TBI
Materials Used for the Synthesis of NPs in TBI Treatment
Limitations of the Use of NPs in TBI Therapy
Conclusion
References
9 Application of Nanoemulsions in Food Industries: Recent Progress, Challenges, and Opportunities
Introduction
Components of Nanoemulsions
Oil Phase
Aqueous Phase
Stabilizers
Approaches for Nanoemulsion Production
High-Energy Approaches
Low-Energy Approaches
Novel Approach for the Production of Nanoemulsion
Applications of Food-Grade Nanoemulsions
Encapsulation of Lipophilic Functional Food
Expansion of the Functional Food Sector for the Application of Edible Coatings with Lipophilic Bioactive Substances
Invasion of Nanotechnology and Emulsion in Food Ingredients and Additives
Purple Rice Bran Oil Nanoemulsion Fortification of Frozen Yogurt
Formation of Various Phytosomes and Using Them for Delivery in Herbal Products Without Resorting to Pharmacological Adjuvants
Food Packaging
Use in Confectionary
Comparison of Nanoemulsion from Conventional Methods
Problems and Probable Solutions of Nanoemulsions
Future Trends and Challenges
Regulations and Safety Aspects
Conclusion
Conflict of Interest
Acknowledgments
References
10 Adverse Epigenetic Effects of Environmental Engineered Nanoparticles as Drug Carriers
Introduction
ENP-Based Drug-Delivery Systems
Lipid-Based ENPs
Polymeric ENPs
Inorganic ENPs
Adverse Epigenetic Effects of ENPs
Overview of Epigenetic Toxicity of ENPs
Epigenetic Toxicity of Metallic ENPs
Epigenetic Toxicity of Nonmetallic ENPs
ENP-Induced Epigenetic Toxicity Likely Mediated by ROS
Conclusion
References
11 Engineered Nanoparticles Adversely Impact Glucose Energy Metabolism
Introduction
Biological Toxicity of Engineered Nanoparticles
Engineered Nanoparticles Alter Glucose Metabolism
Engineered Nanoparticles Alter TCA Cycle
Engineered Nanoparticles Alter Oxidative Phosphorylation
Conclusion
References
12 Artificial Intelligence and Machine Learning of Single-Cell Transcriptomics of Engineered Nanoparticles
Introduction
Impact of Nanoparticles on Single-Cell Transcriptomics and Response Heterogeneity
Overview of Engineered Nanoparticles
Dose-Dependent Heterogeneous Transcriptomic Responses to Quantum Dots
TiO2 Nanoparticles of Different Sizes Elicit Heterogeneous Transcriptomic Responses
AI and ML in scRNA-Seq Data Analysis
Overview of AI and ML in Bioinformatics
MRF in Differential Expression Analysis of scRNA-Seq Data
Deep Learning for Inferring Gene Relationships from scRNA-Seq Dat
Determining Cell Differentiation and Lineage Based on Single-Cell Entropy
Conclusion
References
13 Toxicogenomics and Toxicological Mechanisms of Engineered Nanomaterials
Introduction
Genomic Responses to ENMs
Transcriptomic Responses to ENMs
Conclusion
References
14 Carbon Nanotubes Alter Metabolomics Pathways Leading to Broad Ecological Toxicity
Introduction
Biomedical Application and Toxicity of Carbon Nanotubes
Single-Walled Carbon Nanotubes
Multi-Walled Carbon Nanotubes
Metabolomics Toxicity of Carbon Nanotubes
A Brief of Metabolomic Techniques Used for CNT Toxicity Profiling
NMR-Based Metabolomic Profiling
LC-MS-Based Metabolomic Profiling
Conclusion
References
15 Assessment of the Biological Impact of Engineered Nanomaterials Using Mass Spectrometry-Based MultiOmics Approaches
Introduction
Applications of MS for the Measurements of Proteins, PTMs, Lipids, and Metabolites
Multiomics Investigation of ENM Exposure to Microorganisms
Multiomics Investigation of ENM Exposure Using In Vitro Cell Culture Models
Analysis of ENM Toxicity in Liver-Based Cell Models
Macrophage-Based Studies of ENM Toxicity
Neuronal Cell Models Reveal Potential Mechanisms of ENM-Induced Neurotoxicity
Multiomics Studies Reveal Organ-Specific Toxicity at the Organismal Level
Mechanisms of ENM-Induced Toxicity in the Lung
Elucidation of Response Pathways Following Ingestion of ENMs
ENM-Induced Metabolic Changes in the Gut: Involvement of Multiple Biological Systems
ENM-Induced Metabolic Changes During Embryo Development
Probing the Relationship Between Particle Size and Toxicity in Whole Animal Systems
Conclusions and Perspectives
Acknowledgments
Compliance with Ethical Standards
References
16 Current Scenario and Future Trends of Plant Nano-Interaction to Mitigate Abiotic Stresses: A Review
Abbreviations
Introduction
Synthesis of Nanoparticles
Silver Nanoparticles
Aluminum Oxide Nanoparticles
Copper Nanoparticles
Iron Nanoparticles
Carbon Nanoparticles
Synthesis of Other Metal Nanoparticles
Morphophysiological Effects of Nanoparticles on Plant
Arabidopsis
Rice
Soybean
Wheat
Other Plants
Molecular Mechanism Altered by Nanoparticles
Oxidative Stresses
Energy Regulation
Nanoparticles Interaction with Plants
Nanoparticles Interaction with Soybean
Nanoparticles Interaction with Wheat
Nanoparticles Interaction with Other Plants
Conclusion and Future Prospects
References
17 Latest Insights on Genomic and Epigenomic Mechanisms of Nanotoxicity
Introduction
Mechanisms of Genotoxicity
Direct Genotoxicity
Indirect Genotoxicity
Genomic Consequences of ENM Exposure
Direct DNA Damage
Oxidative Damage
Inflammatory Changes
Impact on DNA Repair Pathways
A Primer on Epigenetic Processes
DNA Methylation
Histone Modifications
ncRNAs
Epigenomic Consequences of ENM Exposure
Apoptosis
Inflammation and Oxidative Stress
Epigenomic Changes and Cancer
Development and Genomic Imprinting
Importance of Duration and Dose of Exposure
Evidence in Humans
Is There a Need for Epigenetic Testing of ENMs?
Importance of Properties of ENMs
Future Perspectives
References
Index
End User License Agreement
List of Tables
CHAPTER 02
Table 2.1 Some examples of...
Table 2.2 Summary of selected...
Table 2.3 Summary of selected...
Table 2.4 Summary of selected...
CHAPTER 03
Table 3.1 A representative list...
Table 3.2 Common EDCs encountered...
Table 3.3 A list of...
Table 3.4 In vitro and...
Table 3.5 A representative list...
Table 3.6 In vitro and...
Table 3.7 List of thyroid...
Table 3.8 The list of...
CHAPTER 05
Table 5.1 In vitro and...
Table 5.2 In vitro and...
Table 5.3 In vitro and...
Table 5.4 Studies on genotoxic...
CHAPTER 06
Table 6.1 Summary of DNA...
Table 6.2 Summary of changes...
Table 6.3 Summary of changes...
CHAPTER 10
Table 10.1 Epigenetic effects of...
Table 10.2 Epigenetic effects of...
Table 10.3 Epigenetic effects of...
CHAPTER 16
Table 16.1 List of nanoparticles...
Table 16.2 Morphophysiological response of...
Table 16.3 Alteration in molecular...
CHAPTER 17
Table 17.1 Summary of mechanisms...
Table 17.2 Genomic effects of...
Table 17.3 Epigenomic effects of...
Table 17.4 Influence of ENM...
List of Illustrations
CHAPTER 02
Figure 2.1 DNA methylation and...
Figure 2.2 Process of the...
CHAPTER 03
Figure 3.1 Mechanism of genomic...
Figure 3.2 Schematic representation of...
Figure 3.3 Changes in the...
Figure 3.4 Modular structure of...
Figure 3.5 Schematic representation of...
Figure 3.6 Modulation of EDCs...
Figure 3.7 Possible xenobiotic-induced...
Figure 3.8 The modular structure...
CHAPTER 04
Figure 4.1 Sources and fate...
Figure 4.2 Major sites and...
Figure 4.3 Schematic diagram showing...
CHAPTER 05
Figure 5.1 Mechanisms of nanomaterial...
Figure 5.2 Main epigenetic events...
Figure 5.3 Potential NMs mediated...
CHAPTER 06
Figure 6.1 TiO2 exposure induces...
CHAPTER 07
Figure 7.1 A schematic representation...
CHAPTER 08
Figure 8.1 Nanoparticle synthesis, materials...
CHAPTER 11
Figure 11.1 Glucose energy metabolism...
CHAPTER 14
Figure 14.1 Carbon nanotubes impact...
CHAPTER 17
Figure 17.1 Cellular and nuclear...
Figure 17.2 Mechanisms of DNA...
Guide
Cover
Title Page
Copyright
Dedication
Table of Contents
List of Contributors
Preface
Acknowledgments
Begin Reading
Index
End User License Agreement
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List of Contributors
Salma M.S. AhmadDepartment of Biological and Environmental Sciences College of Arts and Sciences Qatar University Doha, Qatar
Saleh AlfuraihDepartment of Pharmaceutical Sciences College of Pharmacy Nova Southeastern University Fort Lauderdale, FL, USA
Eid AlshammariDepartment of Biochemistry, Microbiology, and Immunology Wayne State University School of Medicine Detroit, MI, USA
Maryam Al-MansoobDepartment of Biological and Environmental Sciences College of Arts and Sciences Qatar University Doha, Qatar
Najlaa Al-ThaniResearch and Development Department Barzan Holdings Doha, Qatar
Rais A. AnsariDepartment of Pharmaceutical Sciences College of Pharmacy Nova Southeastern University Fort Lauderdale, FL, USA
Piyoosh Kumar BabeleCollege of Agriculture Rani Lakshmi Bai Central Agricultural University Jhansi, Uttar Pradesh, India
Ravi Kant BhatiaDepartment of Biotechnology Himachal Pradesh University Shimla, Himachal Pradesh, India
Delia CavalloDepartment of Occupational and Environmental Medicine, Epidemiology and Hygiene Italian Workers’ Compensation Authority-INAIL Monte Porzio Catone, Rome, Italy
Ramesh ChaudhariBiological and Life Sciences, School of Arts and Sciences Ahmedabad University (Central Campus) Ahmedabad, Gujarat, India
Pieranna ChiarellaDepartment of Occupational and Environmental Medicine, Epidemiology and Hygiene Italian Workers’ Compensation Authority-INAIL Monte Porzio Catone, Rome, Italy
Aureliano CiervoDepartment of Occupational and Environmental Medicine, Epidemiology and Hygiene Italian Workers’ Compensation Authority-INAIL Monte Porzio Catone, Rome, Italy
Nicholas DayBiological Sciences Division Pacific Northwest National Laboratory Richland, WA, USA
Valentina Del FrateDepartment of Occupational and Environmental Medicine, Epidemiology and Hygiene Italian Workers’ Compensation Authority-INAIL Monte Porzio Catone, Rome, Italy
Anna Maria FresegnaDepartment of Occupational and Environmental Medicine, Epidemiology and Hygiene Italian Workers’ Compensation Authority-INAIL Monte Porzio Catone, Rome, Italy
Matthew J. GaffreyBiological Sciences Division Pacific Northwest National Laboratory Richland, WA, USA
Mario GanauNeuroscience Division Oxford University Hospitals Oxford, UK
Mohammad Z. HaiderDepartment of Basic Medical Sciences College of Medicine, QU Health Qatar University Doha, Qatar
George HammonsDivision of Biochemical Toxicology National Center for Toxicological Research U.S. Food & Drug Administration Jefferson, AR, USA
Vratko HimičNeuroscience Division Oxford University Hospitals Oxford, UK
and
University of Oxford Medical School Oxford, UK
Saleem JavedDepartment of Biochemistry Aligarh Muslim University Aligarh, India
Hafiz Muhammad JhanzabDepartment of Agronomy The University of Agriculture Dera Ismail Khan Khyber Pakhtunkhwa, Pakistan
Pius JosephMolecular Carcinogenesis Laboratory Toxicology and Molecular Biology Branch Health Effects Laboratory Division National Institute for Occupational Safety and Health (NIOSH) Morgantown, WV, USA
Firas KobeissyProgram for Neurotrauma, Neuroproteomics & Biomarkers Research Departments of Emergency Medicine University of Florida Gainesville, FL, USA
Setsuko KomatsuFaculty of Environment and Information Sciences Fukui University of Technology Gakuen, Fukui, Japan
Ashutosh KumarBiological & Life Sciences, School of Arts & Sciences Ahmedabad University (Central Campus) Ahmedabad, Gujarat, India
Gianfranco K.I. LigarottiInstitute of AeroSpace Medicine Milan, Italy
Beverly Lyn-CookDivision of Biochemical Toxicology National Center for Toxicological Research U.S. Food & Drug Administration Jefferson, AR, USA
Ghazala MustafaDepartment of Plant Sciences Quaid-i-Azam University Islamabad, Pakistan
Yadollah OmidiDepartment of Pharmaceutical Sciences College of Pharmacy Nova Southeastern University Fort Lauderdale, FL, USA
Stuti PatelDepartment of Biology University of Florida Gainesville, FL, USA
Vishva PatelBiological and Life Sciences, School of Arts and Sciences Ahmedabad University (Central Campus) Ahmedabad, Gujarat, India
Marta PogribnaDivision of Biochemical Toxicology National Center for Toxicological Research U.S. Food & Drug Administration Jefferson, AR, USA
Wei-Jun QianBiological Sciences Division Pacific Northwest National Laboratory Richland, WA, USA
Saura C. SahuFORMER (retired) emplyee of the Food and Dug Administaration Columbia, MD, USA
Abdullah ShaitoBiomedical Research Center College of Medicine and Department of Biomedical Sciences at College of Health Sciences Qatar University Doha, Qatar
Saghir A. ShakilToxInternational Inc. Hilliard, OH, USA
and
Department of Biomedical and Biological Sciences Aga Khan University Karachi, Pakistan
Kamran ShekhToxicology Consultant Yordas Group (Canada Office) Hamilton, ON, Canada
Nikolaos SyrmosSchool of Medicine Aristotle University of Thessaloniki Greece
Brian D. ThrallBiological Sciences Division Pacific Northwest National Laboratory Richland, WA, USA
Cinzia Lucia UrsiniDepartment of Occupational and Environmental Medicine, Epidemiology and Hygiene Italian Workers’ Compensation Authority-INAIL Monte Porzio Catone, Rome, Italy
Carlos WellsDivision of Biochemical Toxicology National Center for Toxicological Research U.S. Food & Drug Administration Jefferson, AR, USA
Alexander YangDepartment of Biochemistry, Microbiology, and Immunology Wayne State University School of Medicine Detroit, MI, USA
Nouran YonisDepartment of Biochemistry, Microbiology, and Immunology Wayne State University School of Medicine Detroit, MI, USA
Zhe YangDepartment of Biochemistry, Microbiology, and Immunology Wayne State University School of Medicine Detroit, MI, USA
Farhat YasmeenDepartment of Biosciences University of Wah Wah Cantt, Pakistan
Tong ZhangBiological Sciences Division Pacific Northwest National Laboratory Richland, WA, USA
Yingxue ZhangDepartment of Biochemistry, Microbiology, and Immunology Wayne State University School of Medicine Detroit, MI, USA
Preface
Engineered nanomaterials are products of the twenty-first century. Because of their superior physiochemical properties, they are applied in different areas of development, such as agriculture, energy, environment, medicine, biotechnology, and material science. They have great potential for improving human life. They are used in a wide range of consumer products, such as cosmetics, drugs, medical devices, paints, nanofabrics, and electronics. Humans are exposed to engineered nanomaterials every day. The effect of their long-term exposure is of public concern. In spite of their beneficial impacts on human life, much remains to be known about their safety. They appear to impact human life both ways, good and bad. Humans benefit from them in many ways, but at the same time, public concern about their safety continues to exist. At the moment, it is up to us to trust nanoscience or avoid it as much as possible.
It is my sincere hope that the up-to-date information presented in this monograph will serve as a stimulus to investigators interested in the impact of engineered nanomaterials on genomics and epigenomics.
The importance of research in this area of scientific discipline is evidenced by the increasing number of contributions published each year. It becomes increasingly clear that developments in this field are moving so rapidly that new means are needed to report the status of ongoing research activities. The contributions presented in this monograph represent a collaborative effort by international experts working in this emerging field of science.
The main purpose of this book is to assemble up-to-date, state-of-the-art information on the impact of engineered nanomaterials in genomics and epigenomics presented by internationally recognized experts in a single edition. Therefore, I sincerely hope that this book will provide an authoritative source of current information on this area of nanoscience and prove useful to the scientists interested in this scientific discipline throughout the world. However, it should be of interest to a variety of other scientific disciplines, including toxicology, medicine, and pharmacology, as well as drug and food sciences.
Saura C. Sahu, Ph.D.
Columbia, Maryland, USA
Acknowledgments
I am indebted to the internationally recognized experts who shared my enthusiasm for the field of nanoscience and contributed generously to this book. They were selected from academia, industry, and government for their expertise in their areas of research. Their work speaks for itself, and I am grateful to them for their strong commitment, cooperation, and excellent contributions in their areas of expertise.
I thank John Wiley & Sons Ltd, particularly Jenny Cossham and Elke Morice-Atkinson, for their excellent help, cooperation, support, and assistance for the timely publication of this book. Wiley published my first book, Hepatotoxicity: From Genomics to in vitro and in vivo Models, 682 pages, in 2007. Since then, Wiley has published more than a dozen of my books in different, new, emerging, and developing areas of modern toxicology and medicine (i.e. nanotoxicology, systems toxicology, toxicogenomics, epigenomics, microRNAs, stem cells). Wiley published my last book, Genomic and Epigenomic Biomarkers of Toxicology and Disease: Clinical and Therapeutic Actions, in 2022, and is currently publishing my book titled Impact of Engineered Nanomaterials in Genomics and Epigenomics. I express my gratitude to John Wiley & Sons Ltd.
Saura C. Sahu, Ph.D.
Columbia, Maryland, USA
1 Impact of Engineered Nanomaterials in Genomics and Epigenomics
Saura C. Sahu
FORMER (retired) emplyee of the Food and Dug Administaration Columbia, MD, USA
Nanotechnology: A Technological Advancement of the Twenty-First Century
Nanotechnology is a new technological development of the twenty-first century. The US National Nanotechnology Initiative (NNI) defines nanotechnology as “the understanding and control of matter at dimensions between approximately 1 and 100 nm, where unique phenomena enable novel applications” (NNI 2014; NSTC 2011). Nanotechnology is a new and developing technology. The ratio of the surface area to volume of a nanoparticle is high compared with its larger counterpart (Roduner 2006). This property makes them more reactive compared with the larger particles. Engineered nanomaterials are used in a wide range of consumer products (Shen et al. 2013), such as cosmetics, drugs, medical devices, paints, nanofabric clothes, and electronics because of their superior physiochemical properties. They demonstrate better magnetic, electrical, optical, and thermal properties compared with their larger counterparts. Therefore, they have found useful applications in different areas of development, such as agriculture, energy, environment, medicine, biotechnology, and material science. They have shown great potential for impacting human life because of their beneficial properties.
Genomics and Epigenomics
The National Institute of Health (NIH) defines genomics as “the study of all of a person’s genes (the genome), including interactions of those genes with each other and with the person’s environment”. The National Cancer Institute (NCI) defines genomics as an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is defined as a complete set of DNA, including all of its genes in an organism. The genome contains all the information needed for an organism to develop and grow. The global analysis of gene expression profiles provides a comprehensive view of toxicity and disease.
In genomic mechanisms of toxicity and disease, the genomic DNA sequence is altered by the chemical exposure. Such modified genomic DNA sequences are not cell and tissue specific. However, in some cases, toxicity and diseases are caused by DNA modifications due to chemical exposure, but in the absence of any direct alteration in genomic DNA sequence. Such DNA modifications without direct alterations in genomic DNA sequences are known as epigenomics, where DNA methylation regulates gene expression without direct alteration in the DNA sequence. In DNA methylation, gene expression occurs at the cytosine dinucleotide when a methyl group is added at position-5 producing methylcytosine (de Gannes et al. 2020). Unlike genomic changes, the epigenetic changes are cell and tissue specific. The epigenetic changes may be heritable and nonheritable. DNA methylation is associated with several human diseases including cancer.
The epigenome is defined as heritable biological information contained outside the DNA sequence (Dolinoy and Jirtle 2008). It consists of DNA methylation, histone modifications, and microRNAs. Noncoding RNAs (ncRNAs) regulate gene expression at the transcriptional or posttranslational levels without changing the genomic DNA sequence.
Beneficial Impacts of Engineered Nanomaterials on Human Life
Engineered nanomaterials demonstrate a huge potential to transform human life for the better. Their use in consumer products is increasing rapidly. They are used in our food, cosmetics, medicine, and agriculture (Sahu and Hayes 2017). They are used in our water filters to remove microorganisms, such as bacteria from drinking water. They are used in water treatment systems. They are used to make our fabrics fire resistant and to prepare plastic bottles for daily use. They are used in cosmetics, sunscreens, pharmaceuticals, medicine, and medical devices. They are used for drug delivery in chemotherapy and as nanosensors for patients. They are used in computer circuits and for fuel efficiency in vehicles. Engineered nanomaterials are used in vehicles and sports equipment to make them lighter, stronger, and chemical resistant. They are used in solar plastics to collect solar energy. They are used to clean up chemical spills and airborne pollutants.
Potential Adverse Health Effects of Engineered Nanomaterials
Humans are exposed to engineered nanomaterials every day. Therefore, the health effects of these nanomaterials are of public concern. In spite of the various beneficial impacts of engineered nanomaterials on human life, our knowledge of engineered nanomaterials is not complete. We must keep in mind that nanoscience is a developing new science. Many things remain unknown. We do not know much about long-term effects engineered nanomaterials. We do not know much about their safety. Many questions about their potential effects on our health, planet, and ecosystems come to our mind. At the moment, they are unregulated. There are no recognized standards for producing and handling them. Are they safe? Are they double-edged swords? Such concerns will continue to exist in our minds until more is known about them. At the moment, it is up to us to trust nanoscience or avoid it as much as possible.
The molecular mechanisms of gene–environment interactions have attracted widespread interest in recent years. These effects may be of genomic and/or epigenomic in nature, highlighting potential molecular targets following the exposure of engineered nanomaterials.
Thai et al. (2016) published the first report on genomic effects of titanium dioxide nanomaterials in an in vitro study using human liver HepG2 cells. This study linked some of the in vitro canonical pathways to in vivo adverse outcomes: NRF2-mediated response pathways to oxidative stress, acute phase response to inflammation, cholesterol biosynthesis to steroid hormones alteration, fatty acid metabolism changes to lipid homeostasis alteration, G2/M cell checkpoint regulation to apoptosis, and hepatic fibrosis/stellate cell activation to liver fibrosis.
Bicho et al. (2020) in a multigenerational study demonstrated epigenetic effects of copper oxide nanomaterials in environmental species Enchytraeus crypticus. Using gene expression analyses, they showed changes in the epigenetic gene targets, depending on the generation and form of copper. Also, they showed its transgenerational effects in postexposure generations. They observed nanoparticle-specific effects indicating differences between organisms exposed to different forms of copper.
Lu et al. (2016) and Sierra et al. (2016) reported the effect of nanomaterial exposure on the mammalian epigenome.
Conclusions
Currently, engineered nanomaterials appear to be double-edged swords. They impact our lives both ways, good and bad. We benefit from them in many ways, but at the same time we are concerned about their adverse health effects. Public concern about their safety will continue until we understand them completely. At the moment, it is up to us to trust nanoscience or avoid it as much as possible.
With regard to the need for a book on the impact of engineered nanomaterials in genomics and epigenomics, the rate of publications during the past few years has demonstrated that the impact of engineered nanomaterials in genomics and epigenomics has attracted widespread interest and, therefore, there is a need for new means to report the updated current status of this developing area of research. As the editor of this monograph Impact of Engineered Nanomaterials in Genomics and Epigenomics, it gives me great pride, pleasure, and honor to introduce this unique book that encompasses many aspects of genomic and epigenomic research never published together before.
References
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2 Molecular Impacts of Advanced Nanomaterials at Genomic and Epigenomic Levels
Kamran Shekh1, Rais A. Ansari2,*, Yadollah Omidi3, and Saghir A. Shakil4,5,6
1 Yordas Group (Canada Office), Hamilton, ON, Canada
2 Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
3 Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
4 ToxInternational Inc, Hilliard, OH, USA
5 Department of Biomedical and Biological Sciences, Aga Khan University, Karachi, Pakistan
6 Institute of Environmental Science and Meteorology, University of the Philippines-Diliman, Quezon City, Philippines
* Corresponding author
Introduction
Nanomaterials (NMs) are generally defined as nanoscale materials that have at least one of their dimensions in the range of 1–100 nm. The terms nanomaterials and nanoparticles (NPs) are often used interchangeably even though these terms are distinct. Nanoparticles, as the name indicates, are spherical particles in the nano-size range, typically 1–100 nm, whereas, NMs include NPs along with other nano-sized objects, such as nanofibers and nanorods (Auffan et al. 2009; Jeevanandam et al. 2018). NMs could be naturally occurring, such as different types of biomolecular particles in the human body that make the foundation of many biomacromolecular structures. Some examples of natural NMs are glucose particles (size approximately 1 nm), DNA (2.2–2.6 nm), ribosomes (25 nm), and antibodies (2–200 nm) (Ménétret et al. 2007; Milo and Phillips 2015; Papazoglou and Parthasarathy 2007; Schaefer 2010; Sinden 2012). Another subtype of naturally occurring NMs, which are often categorized separately, are incidental NMs, which are produced either unintentionally from anthropogenic activities or produced from purely natural processes. Examples of incidental NMs are cosmic dust, volcanic eruptions, forest fires, engine exhaust, building demolition, cigarette smoke, and NMs formed in the environment from various types of plastic waste (Jeevanandam et al. 2018; Kumar et al. 2020). Nanoscale materials that are intentionally produced due to their desirable properties or their application in a specific area are designated as engineered nanomaterials (ENMs) (Yokel and Macphail 2011). ENMs have huge applications in a variety of sectors, including medicine, specialty chemicals, solar batteries, aviation and construction industries, paint, food industry, and electronics, just to name a few (Ali 2020). Due to such huge applications, the use of NMs has risen dramatically in recent years and with high usage, the exposure of humans and the environment to NMs has also significantly increased.
The use of NMs increased tremendously after findings that several key physicochemical properties of matter change significantly when they are produced at the nano-sized range. Some of the key physicochemical changes that happen in the properties of matter at the nanoscale level include increased strength and hardness, decreased melting point, increased heat capacity, and solubility. The key change in the properties of matter at the nanoscale is the significant increase in the surface area. Remarkably, the majority of unique physicochemical properties of NMs can be explained by an increased surface area (Trotta and Mele 2019). Interestingly, the increased surface area of NMs along with their other unique physicochemical properties are also responsible for their unique biological, pharmacological, and toxicological properties.
Classification of NMs
Intentionally produced NMs can be classified in several ways. The most common way to classify NMs is based on their nature, size/dimension, and morphology. Upon the constituent materials, NMs are commonly classified into four types: (i) carbon-based NMs; (ii) inorganic-based NMs; (iii) organic-based NMs; and (iv) composite-based NMs (Majhi and Yadav 2021). Carbon-based NMs are available in different types of morphologies, such as fullerenes, carbon nanotubes, nanofibers, carbon black, and graphene. Inorganic-based NMs include metal and metal oxide NMs, such as AgNPs, AuNPs, FeONPs, SiO2NPs, and ZnONPs. Organic-based NMs are made from organic materials, they do not include carbon-based NMs (Jeevanandam et al. 2018). Composite-based NMs, which are multiphase solid materials with one of the phases, have one, two, or three dimensions of less than 100 nm or structures with nanoscale repeat distances between the phases making up the materials. NMs are also classified based on their size/dimension and they could be zero-dimensional, where all three dimensions of the NMs are in the nanoscale range. Most NPs fall into this category. For one-dimensional NMs, one of the dimensions is in the nanoscale range and the other two dimensions are not. Nanorods and nanotubes fall within this category. The two-dimensional NMs, as the name indicates have two of the three dimensions in the nanoscale range and the third out of the nanoscale range; major examples of this type of NMs are nanofilms and nanolayers. Finally, three-dimensional (3D) NMs have none of its three dimensions in the nanoscale range. Materials such as nanocomposites and bundles of nanotubes are examples of 3D NMs (Jeevanandam et al. 2018).
Absorption and Distribution of NMs
Inhalation Exposure
Inhalation is considered the most relevant route of possible exposure for NMs. Depending on the size and physicochemical properties, NMs can be deposited at different locations throughout the respiratory tract. Nanoscale particles can reach the deepest part of the lungs, i.e., gas exchange surfaces, and larger particles are deposited further up. Similarly, large-diameter fibers are deposited in the respiratory branches whereas smaller-diameter fibers move further down and may reach up to the alveoli. Very long fibers (high aspect ratio) with smaller diameters may, however, remain stuck in upper airways (Hoet et al. 2004; Lippmann 1990; Oberdörster 2001). NMs deposited in the lungs are cleared through physical translocation as well as chemical clearance. NMs that are soluble in physiological fluids are chemically dissolved and the process is much faster compared to the physical translocation. NMs, which are relatively insoluble in the lung environment, are cleared through physical transition via mucociliary function.
The first step after the inhalation of NMs is the NMs’ interaction with the phospholipids and proteins in the lining fluid of the respiratory epithelium. Upon the mucociliary action, the ciliated epithelial cells in the bronchi continuously move the NMs-associated mucosal entity into the pharyngeal region resulting in the possible clearance of NMs from the lungs (Semmler et al. 2004; Takenaka et al. 2001). Another route of lung clearance for NPs of particle size <10 microns is phagocytosis in the alveolar region, where macrophage cells can phagocyte the accumulated NPs. During the process of phagocytosis, the NPs are digested in the lysosomes of phagocytes, and the digested material is removed by exocytosis (Buzea et al. 2007).
Notably, the inhaled NMs can also be transported to the nervous system through the olfactory nerve system. The nasal, tracheal, and bronchial regions are rich in nerve endings; thus, such routes can be a potential transportation path for NMs (Oberdörster et al. 2005a). In monkeys, silver-coated gold nanoparticles were demonstrated to migrate to the olfactory nerves when instilled nasally (Oberdörster et al. 2005a). Similarly, magnesium oxide (MgO) NPs and carbon NPs have also been shown to be translocated to the olfactory nerves when given to rats through the inhalation route (Elder et al. 2006; Oberdörster et al. 2002). The olfactory region is the only part of the body where the central nervous system and peripheral environment are in direct contact with each other, and chemicals absorbed through the olfactory system circumvent the blood-brain barrier (BBB) and directly reach the brain (Selvaraj et al. 2018). Alternatively, NMs can access the central nervous system by crossing the BBB which selectively controls the inward and outward traverse of substances in the brain. In this line, BBB has been shown to possess selectivity toward cationic NPs (Lockman et al. 2004). For example, AgNPs injected subcutaneously in rats have been shown to reach the brain through BBB (Hirst et al. 2013). Similarly, titanium dioxide (TiO2)NPs when administered intragastrically, accumulate in the hippocampus region of the brain (Hu et al. 2011).
Oral Exposure
Two NMs that are highly used in products for dietary consumption are TiO2NPs and silicates. NMs used in pharmaceuticals and oral cosmetics are also subjected to exposure through the oral route. Additionally, NMs cleared through mucociliary clearance also eventually reach the gastrointestinal (GI) tract. The absorption of particles through the GI tract is a size-dependent phenomenon that decreases with the increasing size of the NMs (Jani et al. 1990). The time to cross the mucosal layer of the intestinal epithelium seems to be also dependent on the size (Hoet et al. 2004). Only NPs, which cross the mucus layer and reach enterocytes, can be absorbed. The mucus layer is in general negatively charged; therefore, diffusion of NMs through the mucus layer is charge dependent as well, where positively charged materials are trapped and negatively charged materials are diffused with relative ease and reach epithelial enterocytes (Hoet et al. 2004).
Dermal Exposure
Studies have shown that NMs are capable of penetrating through the stratum corneum, the outer portion of the epidermis, which is composed of a keratinized layer of dead cells (Borm et al. 2006; Oberdörster et al. 2005b). In vitro experiments have also proved intracellular penetration of NPs (Monteiro-Riviere et al. 2005). Although it is still debatable whether NMs can penetrate through unbroken skin, the penetration of NMs through hair follicles and broken skin are well-known pathways of their uptake. For example, TiO2NPs used in commercially available sunscreen products showed higher penetration in hairy skin, indicating that hair follicles possibly provide an additional route for the absorption of TiO2NPs (Tsuji et al. 2006).
Circulatory Distribution
Studies have shown that the circulatory distribution of NMs is highly size- and material-dependent, in which metallic NPs of size less than <30 nm can most readily enter the circulatory system (Donaldson et al. 2005; Liu et al. 2006; Oberdörster et al. 2005b; Takenaka et al. 2001). When the exposure happens through inhalation, NMs of <20 nm diameter are cleared rapidly from the lungs compared to larger particles and hence these smaller particles enter rapidly into the circulatory system (Takenaka et al. 2001). AuNPs, TiO2NPs, and AgNPs all with a diameter ≤30 nm have been shown to translocate rapidly through the blood to organs, such as the brain, liver, heart, kidney, and spleen (Geiser et al. 2005; Oberdörster et al. 2005a; Takenaka et al. 2001). On the other hand, very little information regarding the rapid circulatory translocation of nonmetallic NMs are available and the results are contradictory. For example, some studies show no translocation of carbon NPs of various sizes ranging between 5 and 100 nm, but some studies show rapid and extensive translocation of nonmetallic NPs of sizes ranging from 5 to 30 nm (Brown et al. 2002; Mills et al. 2006; Nemmar et al. 2002a,b; Oberdörster et al. 2002; Wiebert et al. 2006a,b). In terms of the mechanism of NMs' circulatory distribution, it is known that NMs are taken up by all major blood cells. The uptake of NPs by red blood cells (RBC) is primarily determined by the size of NPs, whereas the charge seems to be the primary determinant of NPs uptake in platelets (Nemmar et al. 2008; Peters et al. 2006).
Accumulation of NMs in Organs
Although endothelial cells of the vascular system are supposed to be a physical barrier to nanoscale particles, they have been shown to cross different types of barriers. For example, ferritin molecules of ~10 nm were detected in the deep brain when injected into the cerebrospinal fluids of rats (Buzea et al. 2007). AgNPs (4–10 nm in diameter) were accumulated in critical organs (e.g., the liver, kidney, and heart) of rats through blood circulation following inhalation exposure (Takenaka et al. 2001). Similarly, NMs generated from wearing dental bridges were accumulated in the liver and kidney through circulatory distribution after absorption from the GI tract; particles accumulated in the liver and kidney were 20 and <6 μm, respectively. The accumulation of NMs has also been shown to occur after oral exposure. For example, when rats were fed with polystyrene, spheres ranging from a few nanometers to a few micrometers in size were distributed to organs, including the liver and spleen when the particle size was <300 nm (Jani et al. 1990).
Major Adverse Effects of NMs
As discussed above, inhalation is the most relevant route of exposure to NMs and the clearance of NMs from the lungs is the key factor in determining the adverse effects of NMs in the lungs as a high lung NM burden may lead to toxicological effects. Upon continuous exposure, the insoluble NMs accumulate rapidly following the saturation of the mucociliary elimination mechanisms. When the NM accumulation reaches a level that is beyond the saturation point of the phagocytosis in the lungs, it leads to adverse effects. The most common effect of NMs exposure to the lungs is the induction of inflammation, epithelial cell proliferation, fibrosis, emphysema, and tumor (Borm et al. 2004; Dasenbrock 1996; Driscoll et al. 1996; Ferin 1994; Nikula et al. 1995; Oberdörster et al. 1994). The mechanisms behind the effects of NMs on the lung are not well known but the generation of reactive oxygen species (ROS) has been indicated to play a key role. For example, carbon nanotubes (CNTs) produce ROS both in vitro and in vivo (Oberdörster et al. 2005a). In general, it is suggested that NMs generate ROS either by directly interfering with the cellular respiratory pathways or by the activation of macrophages. The enhanced oxidative stress leads to alteration in intracellular calcium signaling that eventually leads to the depletion of calcium levels impairing macrophages. Reduced phagocytosis in the lungs leads to interaction between NMs and epithelial cells resulting in inflammation, further enhancing oxidative stress, cell injury, and other morphological effects (Donaldson and Stone 2003; Risom et al. 2005).
Similar to the lungs, many of the adverse effects on the brain (e.g., various neurodegenerative diseases) have been shown to originate from excessive oxidative stress or due to alteration in the homeostasis of trace elements. Several NMs have been shown to cause damage to the nervous system. Although mechanisms of these toxic effects are not well known, oxidative stress and inflammation could be potential mechanisms. AgNPs can damage BBB and cause neuronal harm when injected subcutaneously into rats (Tang et al. 2009). TiO2NPs can also cause brain damage, specifically imposing detrimental impacts on glial cells (Ma et al. 2010).
Under normal conditions, blood is in a balanced state between clotting and bleeding and the balance is critical for human health. The tendency of blood to maintain a balance between clotting and lysing of such clots is known as “hemostatic balance”. The hemostatic balance is dictated by a balance between procoagulant and anticoagulant factors. Any disturbance in the hemostatic balance leads to either bleeding or clotting. Platelets, RBCs, various protein factors, and enzymes are the components that play key roles in hemostatic balance. When NMs reach the bloodstream, they may interact with coagulation, anticoagulation, and fibrinolytic systems, which may lead to dysregulation of the hemostatic balance. CNTs have shown to induce platelet activation and aggregation in some in vitro studies and it has also shown to cause vascular thrombosis in an in vivo study in rats (Radomski et al. 2005; Semberova et al. 2009). CNT has also shown procoagulant activities in some in vitro studies (Luyts et al. 2014). AgNPs have been shown to cause endothelial dysfunction, reduced platelet adhesion and aggregation, and enhanced venous thrombosis formation in a couple of in vitro studies (Ragaseema et al. 2012; Sun et al. 2016). Ag nanowires have been shown to reduce RBC aggregation in some in vitro studies (Kim and Shin 2014). Au nanoparticles have demonstrated a size-dependent effect where 68 nm NPs showed no effect on platelet, whereas 20 nm NPs showed platelet activation (Deb et al. 2011). FeONPs induced RBC aggregation and platelet aggregation in some in vitro studies (Achilli et al. 2016; Ran et al. 2015); however, contradictory results are also found in the literature, where FeONPs showed suppression of platelet aggregation in an in vitro study (Cabrera et al. 2020). Several in vitro studies with silica have shown a vast variety of effects on the circulatory system including NO imbalance, increased coagulation factors, decreased anticoagulant factors, shortened coagulation time, increased platelet activation, and aggregation (Corbalan et al. 2012; Feng et al. 2019; Gryshchuk and Galagan 2016; Guo et al. 2015). TiO2NPs have also shown size-dependent effects on the circulatory system. TiO2NPs (4–6 nm in diameter) have shown increased platelet aggregation both in vitro and in vivo, whereas particles ~40 nm showed no effects (Bihari et al. 2010; Nemmar et al. 2008). ZnONPs have shown procoagulant activity and increased factor VIII levels (Luyts et al. 2014).
Inhalation of NMs also causes cardiorespiratory diseases. TiO2NPs have been shown to accumulate in the heart of zebrafish (Chen et al. 2011) causing inflammation and necrosis of heart cells. Molecular effects induced by TiO2 exposure in cardiac muscles are increased ROS levels and increased DNA peroxidation. Additionally, TiO2 reduced the expression of antioxidant enzymes (Sheng et al. 2013). Cardiac injury biomarkers were also shown to increase after oral administration of TiO2. These biomarkers included creatine kinase and lactate dehydrogenase (Bu et al. 2010). Several other NMs, such as ZnONP, AgNP, carbon NPs, and silica NPs, have also been shown to cause several myocardial damage (Bostan et al. 2016). ZnONPs have been suggested to cause myocardial toxicity through their effect on the calcium metabolism in cells. AgNP accumulates in myocardial cells after exposure, causing induction in oxidative stress. Carbon NMs cause histological damage in the left ventricle by increasing the level of injury biomarkers and a decrease in protective thiols in rodents (Ge et al. 2012; Shvedova et al. 2014). Several detailed reviews are available, covering the toxicity of various NMs (Sharifi et al. 2012; Srivastava et al. 2015). Table 2.1 presents some of the main toxicity of various NMs.
Table 2.1 Some examples of the toxicity of nanomaterials.
Nanomaterial
Effects
Experimental model
References
MWCNT
1) DNA damage
2) Cytotoxicity
3) Spleen toxicity
4) Inflammatory response
1) Lung cells
2) Rat glioma cells
3) Mice
4) Rats
(Deng et al. 2009; Guo et al. 2012; Han et al. 2012; Muller et al. 2009)
SWCNT
1) Neuronal toxicity
2) Inflammatory response
3) Reduced cell proliferation and adhesive ability
1) Chicken embryo
2) Human macrophage cells
3) HEK293 cells
(Belyanskaya et al. 2009; Cui et al. 2005; Fiorito et al. 2006)
C60 fullerene particles
1) Pulmonary toxicity
2) Genotoxicity
1) Rats
2) Bacterial cells
(Fujita et al. 2009; Zhang et al. 2009)
ZNONPs
1) Cytotoxicity
2) Delayed apoptosis
3) Changes in the expression of cell adhesion molecules
1) Human pulmonary cell line
2) Human neutrophils
3) Human lymphocytes
(Goncalves and Girard 2014; Lozano-Fernández et al. 2014; Wang et al. 2015)
TiO
2
NPs
1) Oxidative stress
2) DNA damage
3) Changes in the expression of cell adhesion molecules
4) Cytotoxicity
1) Human gastric cells
2) Human gastric cells
3) Human lymphocytes
4) Mice skin cells
(Botelho et al. 2014; Jebali and Kazemi 2013; Lozano-Fernández et al. 2014)
AgNPs
1) Oxidative stress and cytotoxicity
2) Cell injury and dysfunction
1) Human colon carcinoma cells
2) Human umbilical endothelial cells
(Miethling-Graff et al. 2014; Shi et al. 2014)
Known Cellular and Nuclear Uptake Mechanisms for Nanoparticles
A mechanistic understanding of cellular and nuclear uptake is essential for interpreting several aspects of NMs such as therapeutic efficacy and toxicity as well as the mechanism of action of toxicity. The cellular uptake as well as uptake within different cellular compartments/organelles depends on several physicochemical characteristics of the NMs. Some of these characteristics are size, shape, charge, partition coefficient, and the nature of surface coatings. The predominant mechanism of NM cellular uptake is vesicular trafficking through endocytosis and/or transcytosis. Several types of endocytosis mechanisms operate in cells. These types of endocytic pathways are clathrin-mediated endocytosis, caveolae-mediated endocytosis, phagocytosis, macropinocytosis, and pinocytosis.
Both clathrin- and caveolae-mediated endocytosis are receptor-based mechanisms and are operated in many types of cells to internalize different substrates, including viruses and NPs. Different types of cell receptors are involved in clathrin-mediated endocytosis, such as transferrin receptors, lipoprotein receptors, epidermal growth factor receptors, and beta-adrenergic receptors (Park and Oh 2014). The process of clathrin-mediated endocytosis is complex and involves the formation of the coated pit by nucleation of relevant cytoplasmic proteins followed by the invagination of the plasma membrane. Thereafter, an intracellular vesicle is formed by cutting and separating the invagination from the plasma membrane. The clathrin-mediated endocytosis proceeds through entrapment and internalization of the NPs in the vesicles (Muñoz and Costa 2012). Caveolae-mediated endocytosis proceeds through the formation of flask-shaped vesicles that are stabilized by a caveolin protein-based coat (Kaksonen and Roux 2018). Phagocytosis processes are undertaken mainly in immune cells, such as macrophages, dendritic cells, and neutrophils. Phagocytosis is primarily meant to clear pathogens and diseased cells. Nanoparticles have also been shown to be cleared through phagocytosis. The process of phagocytosis begins with the interaction between the foreign body and the phagocyte receptors such as Fc receptor, which leads to opsonization and adsorption of immunoglobulin (Sahay et al. 2010; Stuart and Ezekowitz 2005). Macropinocytosis is an uptake mechanism in many types of cells for extracellular fluid and solutes. This process is mediated through actin in which NPs become entrapped in vesicular structures and hence are transported intracellularly (Palm 2019).
The size of an NM and the type of the cell are crucial determinants of the endocytic mechanism in cells exposed to it. Nanoparticles (e.g., SiO2NPs and CNTs) ranging between 120 and 150 nm are predominantly taken up via clathrin- or caveolin-mediated endocytosis. However, NPs of 250 nm to 3 μm have been shown in vitro to be taken up through phagocytosis, for example, polystyrene, PEGelyated gold nanorods [caviston from fbioe] (Foroozandeh and Aziz 2018). NMs with a size of a few to several hundred nanometers are internalized via macropinocytosis, which, as discussed above, is a generalized process to take up fluids along with particles into the cells from the extracellular environment (Lu et al. 2009; Park and Oh 2014). Some NMs internalized through macropinocytosis are micron-sized polystyrene and lipid NMs (Behzadi et al. 2017).
In comparison with the mechanistic understanding of the cellular uptake of NMs, the uptake into the nucleus is not that well understood. ENMs usually utilize nuclear localization sequences (NLS) to achieve the nuclear localization of NMs. An NLS is an amino acid sequence that naturally acts as a tag for proteins found in cells for their transport to the nucleus (Lu et al. 2021). Molecules that are larger than 10 nm are selectively transported through nuclear pore complexes after they are tagged with NLS (De Robertis et al. 1978; Dingwall et al. 1982). It has been shown that AuNPs coated with NLS are transported into the nucleus via NPC, as long as the diameter is up to 26 nm (Dworetzky et al. 1988).
Epigenetic Mechanisms and the Effect of NMs
Epigenetics alter the activity of genes without making any changes in the DNA sequence, and the changes induced by epigenetics can be transmitted to daughter cells (Simmons 2008). It has become clear in recent years that the role played by epigenetics in controlling the phenotype is very critical and should be considered for the adverse effects of xenobiotics. There are three major types of epigenetic modifications: (i) DNA methylation; (ii) modification of histone; and (iii) regulation of noncoding RNAs. NMs have shown to induce all major types of epigenetic effects. Therefore, it is essential to understand each of these mechanisms individually and how NMs affect them.
